The invention is directed to formulations that are able to prevent or treat decreasing platelet cell counts.
Platelets are small cytoplasmic bodies derived from megakaryocytes. They are also called thrombocytes. Platelets are produced in blood cell formation (thrombopoiesis) in bone marrow, by budding off from megakaryocytes. The platelet count in the circulating blood of a healthy person is typically between 150·109 and 400·109 per liter of blood. Newborn babies have a slightly lower level, but are normally within the adult range by three months of age (Thon et al., 2010; Malara et al., 2012).
Platelets are important for hemostasis. Upon vascular injury, platelets instantly adhere to the exposed extracellular matrix resulting in platelet activation and aggregation to form a hemostatic plug (Id.). However, platelets mis-function caused serious problems. Platelets aggregation may lead thrombosis, consequently, leads to atherosclerosis or stroke [Siddiqui et al., ISSN (Online): 1875-533X]. Platelets aggregation is also contribute to cancer metastasis (Reymond et al., 2013).
A low platelet count is a common problem and has serious consequence. A platelet count of less than 150,000/mL is defined as thrombocytopenia. Thrombocytopenia is a common reason for a hematology consult in both the inpatient and outpatient setting (Wong et al, 2012). Thrombocytopenia is encountered across a number of conditions, including immune (idiopathic) thrombocytopenic purpura (ITP), myelodysplastic syndromes (MDS), liver cirrhosis, aplastic anemia, human immunodeficiency virus (HIV) infection, and major cardiac surgery, as well as a host of relevant genetic disorders. Cancer treatments, such as radiation or chemotherapy, also cause thrombocytopenia. The incidence of chemotherapy-induced thrombocytopenia is 21.8%, with the highest frequency seen in patients receiving carboplatin alone or in combination (Id.). Chemotherapy-induced thrombocytopenia often leads to a reduction in chemotherapy, either a postponement or a reduction in the dose or number of chemotherapy cycles. This reduction has serious consequences: when chemotherapy dose was decreased to less than 85% of the target dose in breast cancer patients, overall and relapse-free survival were significantly decreased (Vadhan-Raj S, 2009).
Thrombocytopenia is difficult to manage in the clinic and the consequences can be life threatening (Connell N T, 2012). The most common treatment of thrombocytopenia is platelet transfusion. Platelet transfusions total well over 10 million units per year in the United States, which present a great burden to the US blood community. Platelet transfusion carries the risk of infection, and can be low efficacy due to allo-immunization. Moreover, platelet transfusion is possibly associated with a decrease in the long-term survival of acute leukemia patients because it is possible that it increases the risk of chemoresistant relapse (Rioux-Masse B et al., 2012) Among the cytokines that play a significant role in megakaryopoiesis, IL-11 and thromobopoietin (TPO) have been shown to stimulate megakaryocyte maturation (Broudy V C et al., 1995; Teramura M et al., 1992). Clinical studies have demonstrated that recombinant human IL-11 could correct thrombocytopenia associated with chemotherapy, HCV infection, or early liver cirrhosis in some degree. In randomized, placebo-controlled trial in patients with solid tumors who had previously received platelet transfusion because of myelosuppression, IL-11 reduced the number of patients in need of platelet transfusions by 26%. However, the side effects of rhIL-11 are significant, including edema in more than 50% of patients, dyspnea, atrial arrhythmias, syncope, and fatigue (Tepler I et al., 1996; Fontana V et al., 2008; Ustun C et al., 2002). First generation of thrombopoietic agents were discontinued due to auto-reactive anti-TPO antibodies. TPO-receptor agonists, Romiplostim and Eltrombopag, have shown to increase platelet count in patients with ITP and liver disease. The two drugs require continuous treatments. Romiplostim costs $55,250 per patient per year. Eltrombopag must be taken every day apart from specific meals containing high levels of calcium (for example, milk), which leads to problems with compliance. The side effects are bone marrow fibrosis, thrombosis, and ocular toxicities (Kuter D J et al., 2008; Khellaf M et al., 2011; Bussel J B et al., Kuter D J et al., 2009; Zeng Y et al., 2011). The effect of TPO-receptor agonists in treating chemotherapy-induced thrombocytopenia is inconclusive (Basciano P A et al., 2012). A recent phase II study has shown that Eltrombopag failed to meet primary endpoint in patients receiving chemotherapy for advanced solid tumors due to slow therapeutic response (Kellam A et al., 2010).